Gene Therapy in Hutchinson-Gilford Progeria Syndrome

Project Summary and Abstract
Hutchinson-Gilford Progeria Syndrome (HGPS) is an incurable, uniformly fatal disease involving a point mutation
in a gene called Lamin A (LMNA). Children develop signs of HGPS typically within the two years after birth and
die at a median age of 14, most commonly from progressive atherosclerotic cardiovascular disease. Although
the causal mutation in HGPS was identified 18 years ago, no cures for this disease exist. Programmable base
editing of DNA now enables the previously unprecedented ability to change single nucleotides in DNA and correct
pathogenic mutations with DNA strand breaks. HGPS represents a tractable disease to test base editing,
however it remains completely unknown whether this strategy will improve disease phenotypes associated with
HGPS. As such, there is a critical need to study how DNA base editing alters the molecular defects driving HGPS
in order to determine whether this genome therapy can fulfill its promise to cure disease. Our overall objective
in this proposal is develop adenine base editing (ABE) as a treatment strategy for HGPS. Our central hypothesis
is that ABE-treatment of adult mice can achieve sufficient editing in aortas to reverse vascular pathology through
cell-autonomous effects on survival and clonal proliferation in VSMCs. Our hypothesis is formulated based on
newly published and new preliminary data that demonstrate: 1) scarless correction of the pathogenic mutation
by ABE in patient fibroblasts and in a humanized mouse model of HGPS; 2) prevention of vascular pathology
and recovery of VSMCs at 6 months after ABE treatment of juvenile mice; 3) a significant increase in overall
survival of ABE-treated juvenile animals. The rationale for this project is that validation of base editing therapies
is needed to determine their potential in treating systemic human diseases. To attain our objectives, we will
pursue the following two specific aims: 1) Test whether DNA editing improves vascular pathology in established
disease by treating adult HGPS animals at different ages with a single injection of AAV-ABE; 2) Identify the
mechanism(s) promoting VSMC recovery after ABE treatment. The overall contribution of this work will be to
elucidate how adenine DNA base editing improves phenotypes in HGPS. The central innovation of this proposal
is a conceptual shift in therapeutic treatment of HGPs by focusing on correcting the underlying pathogenic
mutation in cells and tissues.

Grant Number: 5R01HL160970-04
NIH Institute/Center: NIH
Principal Investigator: JONATHAN BROWN